Project Summary HIV-related chronic inflammation is a major contributor to cardiovascular diseases, neurocognitive decline, cancers, metabolic disorders, and reduced life expectancy among people living with HIV. The gastrointestinal (?gut?) immune system is profoundly damaged by HIV and the collection of microorganisms living in and around the gut, called the ?microbiome,? may be altered in HIV infection. This disruption, termed dysbiosis, may be a significant driver of chronic inflammation, playing a critical role in HIV pathogenesis and contributing to negative health outcomes among people living with HIV. However, studies on HIV and the microbiome to date have found mixed results because of small sample sizes, heterogeneous comparison groups, and failure to consider multiple confounding and modifying factors. Use of illicit substances, alcohol drinking, and obesity are pro-inflammatory conditions, often comorbid with HIV, independently associated with serious heath problems, and may also cause dysbiosis. However, studies have not examined the combined impact of HIV, substance use and obesity on microbial dysbiosis. In fact, little research has been done on the effects of substance use on the microbiome, and few studies of HIV and the microbiome have considered any confounders or effect modifiers at all. My dissertation will attempt to shed light on these complex interactions between HIV, comorbidities, and the microbiome by measuring the contributions of HIV, substance use, and obesity to dysbiosis. My research will be carried out using a rich clinical, biological, and behavioral dataset from a cohort of young men of color who have sex with men (MoCSM), approximately half of whom are HIV- infected and substance-using. My dissertation will be the largest study of HIV and the microbiome to date, and I will employ an innovative analytic strategy, inverse probability of treatment weighting, to control for multiple confounding factors in my analyses. Integrating a large amount of clinical and behavioral data into analyses is a novel contribution to the field of microbiome data analysis. This study population, young MoCSM, are at especially high risk for HIV acquisition, poor HIV outcomes and reduced life expectancy. My dissertation will shed light on the drivers of dysbiosis in young MoCSM, which is a necessary step toward designing interventions to reduce HIV-associated chronic inflammation. Ultimately, my research may help reduce HIV- related morbidity and mortality in this vulnerable population.